EX. 3 - Asthma Flashcards by Jenna Tapper

Episodic bronchospasm resulting form an exaggerated bronchoconstrictor response to various stimuli

Asthma

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Asthma is an - of the bronchi

Inflammation

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Episodic bronchospasm causes

Dyspnea, cough, and wheezing

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Asthma affects -% of adults and -% of children

5% adults
7-10% children
(Over 3,000 fatalities a year)

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Types of asthma

Extrinsic (allergic/classical)
Intrinsic

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Extrinsic asthma:

Hypersensitivity rxn induced by exposure to an extrinsic antigen (dust, mold, pollen)
Commonly associated w/other allergy in patient/family members
Onset - early in life
Elevated serum IgE levels and eosinophil count
Driven by TH2 subset of CD4+T cells

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Intrinsic asthma

Nonimmune triggering mechanism (ex. aspirin, viral infection, cold, psychological stress, exercise)
No personal or family history of allergy
Serum IgE levels - normal

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Two phases of extrinsic asthma attacks

Acute bronchoconstriction
(immediate; 30-60 min)
Sustained bronchoconstriction:
(Late; 4-8 hours later after immediate response)

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Acute bronchoconstriction

Immediate asthmatic response (IAR)
Occurs after sensitization
Mediated by IgE, produced in response to exposure of foreign particles
(IgE binds to FcER-1 on mast cells in the airway mucosa

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Re-exposure to the allergen triggers the release of mediators from the mast cells in a process called

mast cell degranulation

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Mast cells release

Histamine
Tryptase
Leukotrienes (LTC4 and LTD4)
Prostaglandin D2 (PGD2)

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Mediators of acute bronchoconstriction cause

Smooth muscle contraction and vascular leakage

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Sustained Bronchoconstriction

Late asthmatic response (LAR)
(3-6hrs after acute)
Caused by Activation of TH2 cells and cytokine production

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Activation of TH2 cells in sustained bronchoconstriction

Ex. IL5, IL9, IL13
Attract and activate eosinophils
Stimulate mucus hypersecretion by bronchial epithelial cells
Stimulate IgE production by B lymphocytes

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Activation of eosinophils

Release major basic protein, (MBP), eosinophil cationic protein (ECP) peroxidase, - causes tissue damage

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Epithelium remodeling

Hyperplasia
Hypersecretion

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Basement membrane remodeling

Thickening

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Smooth muscle remodeling

Hypertrophy

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Pharm treatments in asthma

Sympathomimetics
ICs’s
(^^MOST COMMON^^)
Leukotriene pathway inhibitors
Methylxanthine drugs
Antimuscarinic Agents
Cromolyn and Nedocromil
Monoclonal antibodies

Sympathomimetics are - while ICS’s are -

Relievers, controllers

Sympathomimetics mechanism

Binds to B2 adrenergic receptors in the bronchial smooth muscle
Increases the cAMP concentration -> relax the muscle cellsS

Types of sympathomimetics

-Nonselective
Epinephrine (IV inject. after severe attack)
-B selective (also affects heart - B1)
Isoproterenol (displaced by B2 selective drugs)
-B2 selective
Most common
Short and long acting agonists

B2 Selective agonist SAR

Bulky N subs-> B2 selective
Subs in the phenyl ring -> B2 selective and resistant to COMT
Mostly racemic -R active

B2 Selective agonists Toxicities

Tachycardia, arrhythmias (less)
Skeletal muscle tremors
Induction of tachyphylaxis - reduction in the bronchodilator response upon regular uses

SABA vs LABA use

SABA - PRN for acute attacks LABA - additional therapy for patients currently using inhaled glucocorticoids NOT for acute attacks, but regular daily use No anti-inflam action (**black box warning**) Comonly combined with corticosteroids

Metoproterenol

SABA Resorcinol analogue of isoproterenol Somewhat B2 selective *LEAST POTENT B2 AGONIST* 5-min onset, 4hr duration Good oral bioavailability

Terbutaline

SABA N-t-butyl analogue of metapro Greater B2 selectivity 3-fold greater potency than metaproterenol at B2 receptors Good oral bioavailability

Albuterol

SABA **most widely used** Resistant to COMT 5-min onset, 4-8hr duration of action when inhaled Levalbuterol is R-isomer (Greater potency, more expensive)

Pirbuterol

Analogous to albuterol except the pyridine ring Comparable duration of action as albuterol Less potent than albuterol

Salmeterol

LABA -Available as powder **Greater lipid solubility**; dissolve in cell membranes 20-minute onset and 12hr duration of action

Formoterol

LABA -Available as powder -More rapid onset than salmeterol with a comparable duration of action Resistant to COMT and MAO

Inhaled corticosteroids (ICSs)

Maintenance therapy for persistent asthma Not curative "controller" Effective only so long as they are taken

_ or _ corticosteroids are reserved for severe cases

Oral or systemic

_ is the most effective way to minimize the systemic adverse effects

Inhaled corticosteroids

ICs's Adverse effects:

Candidiasis - can be treated with topical clotrimazole Can be reduced by having patients gargle water and expectorate after each inhaled treatment **Ciclesonide** - 21 ester prodrug, associated with less candidiasis Hoarseness - direct effect of corticosteroids on the vocal cords Long term - use may increase the risk of osteoporosis and cataracts In children, I cm reduction in the growth only for the first year

Produced form arachidonic acid by 5-lipoxygenase Involved in many inflammatory diseases and in anaphylaxis LTB4 - potent neutrophil chemoattractant LTC and LTD4 - responsible for many symptoms of asthma, such as bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion

Leukotrienes

Improve asthma control and reduce the frequency of asthma exacerbations Not as effective as inhaled glucocorticoids Effective when taken orally, easier than inhalation for children Reduce significantly the response to aspirin in aspirin-induced asthma (5-10% of asthma patients)

Leukotriene pathway inhibitors

Zileuton

Leukotriene pathway inhibitor 5-lipoxygenase inhibitor Racemic mix N-hydroxy group is essential for inhibitory activity Good oral bioavailability Alternative to LABA in addition to ICS NOT for acute asthma attack Requires periodic monitoring of **liver**

Monetlukast

Blocks the binding of LTC4, LTD4, and LTE4 to the receptor Once a day dosing Good oral bioavailable Reduces the frequency of asthma exacerbations Little toxicity

Theophylline (most effective; more specific for smooth muscle) Theobromine Caffeine Once a mainstay for asthma tx, replaced by B2 Still used in some countries due to low cost

Methylxanthine drugs

Methylxanthine MOA

Inhibition of phosphodiesterases (PDE3 and PDE4)-> increase in the cellular cAMP concentration -> bronchodilation and suppression of histamine release Block the action of adenosine, which causes bronchoconstriction and the release of histamine Histone deacetylation, which suppresses inflammatory gene expression

Toxicity of Methylxanthine drugs

Nausea, vomiting, tremulousness, arrhythmias Narrow therapeutic index

"Anticholinergic agents" MOA: Stimulation of cholinergic (parasympathetic) nerves causes bronchoconstriction and mucus secretion Antimuscarinic drugs competitively inhibit the action of acetylcholine at muscarinic receptors Clinically valuable patients who are intolerant of inhaled B agonists

Antimuscarinic agents

Ipratropium

Antimuscarinic agent Bronchodilator Quaternary amine derivative of atropine Poorly absorbed into the circulation after inhaled Minimal oral bioavailability Relatively free of systemic atropine-like effects

Cromolyn and nedocromil Once widely used for asthma management, especially in kids **Inhibit mast cell degranulation** No direct bronchodilator action; should be used prophylactically (daily dosing) Poorly absorbed in the systemic circulation; little toxicity; not as potent as glucocorticoids Current use; allergic rhino conjunctivitis eye drops

Mast cell Stabilizers

**Omalizumab** Recognizes the portion of IgE binding to its receptor (FCER-I and FCER-2) on immune cells Inhibits IgE binding to mast cells Reserved for patients with **severe asthma and allergic sensitization**

Anti-IgE monoclonal antibody

IL-5 release from TH2 cells attracts and activates eosinophils Anti-IL-5 monoclonal antibodies (**Mepolizumab and Reslizumab**) Anit-IL-5 receptor monoclonal antibody **Benralizumab** Used as a maintenance therapy of severe asthma in patients with an eosinophilic phenotype

Anti-IL-5 Therapy